A clinical trial for psoriasis with novel single-cell genomic techniques to understand regulatory immunity behind long-term disease remission off drug induced by short-term IL-23 inhibition

使用新型单细胞基因组技术进行银屑病临床试验，以了解短期 IL-23 抑制诱导的药物长期疾病缓解背后的调节免疫

• 批准号: 10340103
• 负责人: Jaehwan Kim
• 金额: $ 16.89万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-18 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10340103
• 关键词: Anatomy; Antibodies; Antigen-Presenting Cells; Biological; Biological Markers; Biological Products; Biopsy; Biopsy Specimen; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Communication; Cells; Chromatin; Clinical; Clinical Trials; Data; Dendritic Cells; Digestion; Disease; Disease Progression; Disease remission; Dose; Enzymes; Epidermis; FOXP3 gene; Gene Expression; Genomics; Goals; Hour; Human; Immune; Immune System Diseases; Immune Tolerance; Immune response; Immunity; Immunobiology; Injections; KLRB1 gene; Lesion; Machine Learning; Mentors; Messenger RNA; Microfluidics; Molecular; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Natural Killer Cells; Outcome; Pathogenicity; Pathologic; Patients; Pharmaceutical Preparations; Phase; Phenotype; Psoriasis; Public Health; Recurrence; Regulation; Regulatory T-Lymphocyte; Research; Skin; T-Lymphocyte; Techniques; Testing; base; cell type; chronic inflammatory disease; clinical application; combinatorial; cytokine; drug clearance; genetic signature; genomic data; healthy volunteer; indexing; innovation; interleukin-23; keratinocyte; melanocyte; novel; predictive modeling; prevent; programs; restoration; single-cell RNA sequencing; skin disorder; transcriptome; transcriptome sequencing

Although highly effective, biologics targeting IL-23/Th17 axis should be continuously injected to suppress recurrence of psoriasis. My long-term goal is to cure psoriasis without recurrence guided by personal immune tolerance. The overall objectives in this application are to (i) identify regulatory immune cell interactions induced by anti-IL-23p19 antibody administration in the skin of patients whose psoriasis is cleared without recurrence and (ii) develop pre-treatment predictive models for psoriasis patients that anticipate disease recurrence after short-term anti-IL-23p19 antibody injection. The central hypothesis is that IL-23p19 inhibition promotes regulatory immune cells in psoriasis patients whose disease is cleared without recurrence, and their pre-treatment single-cell immune signatures are different from those of patients whose disease recurs. The rationale for this project is that molecular evidence of immune tolerance induction by IL-23p19 inhibition in human skin is likely to offer a strong clinical framework whereby new strategies to prevent recurrence of chronic inflammatory diseases can be developed. The central hypothesis will be tested by pursuing two specific aims: 1) Testing the hypothesis that regulatory immune cell interactions are promoted by short-term anti-IL-23p19 antibody administration in the skin of psoriasis patients whose disease becomes clear without recurrence; and 2) Developing predictive models with pretreatment skin biopsy single-cell genomic data that anticipate long-term disease clearance off drug after short-term anti-IL-23p19 antibody administration. To achieve the specific aims, we have recently developed two innovative complementary single-cell approaches to obtain gene expression profiles of heterogeneous immune cells from psoriasis and control skin without enzyme digestion. The first single-cell experimental approach is microfluidic partitioning of emigrating cells from human skin after 48-hour incubation in culture medium without enzyme digestion, which empowers single-cell transcriptomic profiling of heterogeneous immune cells and keratinocytes in different layers of epidermis under ex vivo condition. The second single-cell experimental approach is Combinatorial indexing RNA sequencing, developed by the co-mentor of the proposal, which enables co-profiling transcriptome and single-cell chromatin accessibility. At the completion of the proposed research, our expected outcomes are to have novel single-cell genomic techniques to study immune cell interactions in human skin, defined single-cell gene signatures of regulatory immune cells that are promoted by anti-IL-23p19 antibody administration in psoriasis skin, and the ability to elucidate how pathologic immunity is suppressed at the single-cell level by highly effective biologics. We also expect to have pre-treatment biomarkers that can predict long-term disease clearance off drugs after short-term anti-IL-23p19 antibody administration.

虽然非常有效，但应持续注射靶向IL-23/Th 17轴的生物制剂， 抑制银屑病复发。我的长期目标是治愈牛皮癣不复发的指导下， 个人免疫耐受本申请的总体目标是（i）鉴定调节性免疫 抗IL-23 p19抗体在银屑病患者皮肤中诱导的细胞相互作用 被清除而不复发，以及（ii）开发银屑病患者的治疗前预测模型， 预测短期抗IL-23 p19抗体注射后疾病复发。核心假设是 IL-23 p19抑制促进银屑病患者的调节性免疫细胞， 没有复发，并且他们治疗前的单细胞免疫特征与患者不同 他的病复发了。这个项目的基本原理是免疫耐受的分子证据 在人皮肤中通过IL-23 p19抑制的诱导可能提供强有力的临床框架， 可以开发预防慢性炎性疾病复发的策略。核心假设 将通过追求两个具体目标进行测试：1）测试调节性免疫细胞 银屑病患者皮肤短期给予抗IL-23 p19抗体可促进相互作用 其疾病变得清晰而无复发;和2）开发具有预处理的预测模型 皮肤活组织检查单细胞基因组数据预测了药物治疗后长期疾病清除 短期抗IL-23 p19抗体给药。为了实现这些目标，我们最近开发了 两种创新的互补单细胞方法，以获得异质性的基因表达谱， 免疫细胞来自银屑病和对照皮肤而没有酶消化。第一个单细胞实验 一种方法是在48小时孵育后对来自人类皮肤的迁移细胞进行微流体分配 在没有酶消化的培养基中，这使得单细胞转录组学分析 异种免疫细胞和角质形成细胞在离体条件下在表皮的不同层。 第二种单细胞实验方法是组合索引RNA测序，由 该提案的共同导师，该提案使转录组和单细胞染色质的可及性共同分析成为可能。 在拟议的研究完成后，我们的预期结果是有新的单细胞 研究人类皮肤中免疫细胞相互作用的基因组技术，定义了单细胞基因特征 在银屑病皮肤中通过施用抗IL-23 p19抗体促进的调节性免疫细胞， 以及阐明病理性免疫是如何在单细胞水平上被高效抑制的能力。 生物制品我们还期望有治疗前的生物标志物可以预测长期的疾病清除 短期抗IL-23 p19抗体给药后停药。